(Not Applicable)
The present invention reports a method for efficiently inhibiting angiogenesis and regressing existing blood vessels. More particularly, this invention relates to methods of treating diseases associated with pathogenic angiogenesis and to delivering anti-angiogenic activity in live animals including humans having such diseases.
Angiogenesis is the growth of new blood vessels from previously existing microvessels. The angiogenic process is a natural and regulated process in wound healing, fetal and embryonal development and in the formation of the corpus luteum, endometrium and placenta. These processes are vital to health and growth and are very well regulated by angiogenic promoters and inhibitors. In disease states, however, this regulation can be circumvented and lead to pathogenic angiogenesis. Pathogenic angiogenesis is unwanted angiogenesis and is the target for therapeutic interventions. A number of human diseases are characterized by unwanted angiogenesis. These include cancer, diabetic retinopathy, age-related macular degeneration, the formation of the arthritic panus and in psoriasis.
In cancer, for example, angiogenesis plays a critical role in the survival and metastasis of tumors. Tumors secrete angiogenic factors that promote the division and migration of endothelial cells, which begins the angiogenic process. It has become clear that tumors need to be vascularised to grow and metastasize. If a tumor""s blood supply is curtailed, the tumor will not grow beyond 0.4 mm. Tumor cells, absent an adequate blood supply, ultimately become necrotic and/or apoptotic. Thus blood vasculature and especially new blood vessel growth or angiogenesis is an important aspect of tumor biology. Therapies directed against angiogenesis could lead to the abrogation or alleviation of these diseases.
The pathogenesis and blindness associated with ocular diseases such as diabetic retinopathy and age-related macular degeneration is a direct outcome of unwanted angiogenesis. In ocular tissue, angiogenesis is the most common cause of blindness. Proliferative diabetic retinopathy is characterized by retinal blood vessel incursion of the vitrous. Age-related macular degeneration is a disease of the macula and is distinguished from the dry form by choroidal blood vessel ingrowth penetrating bruchs membrane. Angiogenic pathology is also associated with retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia. Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum and Paget""s disease.
In one feature, this invention relates to a method of inhibiting the vascularization of endothelial cells, the method comprising contacting a cell, tissue or organ which has endothelial cells with an anti-angiogenic amount of a compound of Formula I. Compounds of Formula I have the following general formula: 
In formula I, R1 and R2 are functional groups including, but not limited to, hydroxyi.
In formula I, R3 is a functional group including, but not limited to, hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, hydroxyl, C1-C6-alkoxy, halogen, NO2, NH3, and COOCH3.
In formula I, R4 is a functional group including but not limited to, hydrogen, C1-C6-alkoxy, glucose, B-D-glucopyranose, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, hydroxyl, halogen, NO2, NH3, carbohydrate, amino acid, nucleotide and lipid.
In formula I, R5 is a functional group including but not limited to, hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, hydroxyl, C1-C6-alkoxy, halogen, NO2, NH3, and CH3.
In formula I, X1-X3, are functional groups including, but not limited to, oxygen, sulfur, CH2-, or carboxy, which can be different but preferably are identical functional groups.
In a preferred embodiment of the invention, the compound of formula I is Oleuropein with formula C25H32O13, as described in the tenth edition of THE MERK INDEX with monograph number 6709, and shown in Formula II. 
Plant extract x, which can comprise any of the ethanolic, acetone, inorganic and organic acid or base and/or aqueous extraction of plant extract x contains: Oleouropein, the compound shown in formula II. Plant extract x is derived from plants including but not limited to the leaves, buds, fruit, wood, bark and roots of the olive tree Olea europaea L., the privet tree, Ligustrum obtusifolium (Oleaceae), etc.
In another aspect, this invention relates to a method for potently inhibiting unwanted angiogenesis in a tissue or organ, the method comprising contacting the cell with a an ethanolic, acetone, inorganic and organic acid or base and/or aqueous solution of plant extract x. or a derivative of the ethanolic, acetone, inorganic and organic acid or base and/or aqueous solution or a component thereof, containing Oleouropein, the compound shown in formula II or a derivative thereof as shown in formula I or products of its hydrolysis, which include but are not limited to oleuropein aglycone, elenolic acid, beta-3,4-dihydroxyphenyethyl alcohol and methyl-o-methyl elenolate or a pharmaceutical composition thereof, in an amount sufficient to inhibit angiogenesis. In a presently preferred embodiment, the cell is in a live organism.
In yet another aspect, this invention relates to a method of treating angiogenic-related diseases mediated by or associated with undesired and uncontrolled angiogenesis, the method comprising administering to a live animal an anti-angiogenic compound of the ethanolic, acetone, inorganic and organic acid or base and/or aqueous solution of extract X or a derivative of the ethanolic, acetone, inorganic and organic acid or base and/or aqueous or a component thereof, containing Oleouropein, the compound shown in formula II or a derivative thereof as shown in formula I or products of its hydrolysis, which include but are not limited to oleuropein aglycone, elenolic acid, beta-3,4-dihydroxyphenyethyl alcohol and methyl-o-methyl elenolate or a pharmaceutical composition thereof, solution in a dosage sufficient to inhibit angiogenesis. These methods are useful for ameliorating the effects of conditions that are characterized by abnormal or undesirable angiogenesis or endothelial cell proliferation and/or migration.
Other features, objects and advantages of the invention and its preferred embodiments will become apparent from the detailed description which follows.